Systemic lupus erythematosus (SLE) is often severe, causing nephritis, oral ulcers, arthritis, pericarditis, pleuritis, rashes, strokes, heart attacks, vasculitis, nervous dysfunction, cytopenias, Raynaud's disease, and immune dysfunction. SLE has complex genetics with many genes contributing to the phenotype. This project, AI242717, has established or confirmed 17 different robust genetic effects, including two susceptibility genes. The centerpiece of the competitive renewal is to identify the gene responsible for the autosomal dominant linkage at 5ql4 with SLE in pedigrees containing an SLE affected with autoimmune thyroid disease. This linkage has been established (LOD=4.96) and independently confirmed (LOD=3.15), thereby providing convincing evidence for linkage. The optimal combined twopoint LOD=9.95. Linkage at 5ql4 has been previously reported in autoimmune thyroid disease. We have explored 599 SNPs for association in the linkage interval and have identified a strong candidate gene. Though there much work left to do, the available evidence is particularly convincing (by repetition and independent replication) that a group of markers, spanning 22 kb and presumed to be in linkage disequilibrium with the causative variant(s) of the candidate gene, is strongly associated with SLE. There are many thousands of untested SNPs in the 5ql4 linkage interval from 91 mb to 100 mb available to help find genetic association if subsequent results do not continue to support candidate gene involvement, including 2051 dbSNPs. We plan to identify the candidate gene variants associated with SLE. In addition, four different confirmatory patient groups are available to test the association, hopefully reinforcing unambiguous gene identification. If this project is successful, then the responsible gene at 5ql4 will have been convincingly identified. We will explore the properties of the responsible gene to describe functional variations that work through this gene to generate SLE. Once this work with the responsible gene at 5ql4 is complete we will redeploy the experimental capacity of AI24717 to explore the next most promising linkage. At this time, a linkage at 3p21 found twice, in pedigrees with SLE cigarette smokers and in SLE pedigrees with anti-Ro and anti-La autoantibodies, is the next most convincing. As suggested by the reviewers, other previously presented specific aims have been removed from the resubmitted AI24717-17A1 proposal. The identified genes and resulting more complete genetic model of lupus will provide better understanding of the pathophysiology of lupus, improved prognostic tools for disease assessment in lupus as well as, perhaps, in other autoimmune diseases, and new molecular targets for therapeutics.